Adverse Effects Of Messenger RNA Vaccines

Written by upenn.edu on October 29, 2021. Posted in Current News

The pandemic caused by the novel coronavirus SARS–CoV–2 (commonly called COVID–19) has had a devastating effect worldwide. Pharmaceutical manufacturers and government agencies are working urgently to develop a vaccine against this virus.

The first of these vaccines are expected to gain Emergency Use Authorization from the US Food and Drug Administration this month. Several different products are in development for potential use in the United States (Table 1), and they use different technologies to stimulate the desired immune response in vaccine recipients. The vaccines that are expected to receive authorization for use soonest are based on a novel lipid–encapsulated messenger RNA (mRNA) technology.

The purpose of this Evidence Advisory is to identify and summarize high–level evidence on the safety of mRNA vaccines. Evaluation of the vaccines’ effectiveness is outside the scope of this report. mRNA vaccines used for therapeutic purposes such as those used in cancer or HIV treatment are also outside the scope of this report.

This report may include evidence on mRNA vaccines used against other diseases, including influenza, cytomegalovirus (CMV), rabies, and Zika, thought it will be indirect evidence for the purpose of predicting the safety of SARS–CoV–2 vaccines. Presently, no such vaccines are licensed for use in the United States (1).

Previous CEP Reports

CEP has published a Rapid Guidance Summary on COVID–19 vaccines for women who are pregnant or lactating. The scope was limited to existing guidelines from public health agencies and professional societies, systematic reviews, and medical center policies. The report found that the American College of Obstetricians and Gynecologists and the Society for Maternal–Fetal Medicine sought to balance the possible risks of vaccination with the risks of remaining unvaccinated, and recommended shared decision–making by women and their physicians.

Guidelines from United Kingdom sources recommended against COVID–19 vaccination for women who are pregnant or breastfeeding. Guidance from Penn Medicine and other US medical centers generally followed the ACOG and SMFM positions. Current UPHS policy The University of Pennsylvania Health System does not have any written policy documents relevant to this topic. All UPHS hospitals, outpatient, and home care entities are vaccinating employees against SARS–CoV–2 using mRNA vaccines. The vaccinations are not mandatory.

Methods

CENTER FOR EVIDENCE–BASED PRACTICE PROTOCOL FOR SYSTEMATIC REVIEW SPECIFIC AIM:
Identify and summarize high–level evidence relating to the safety of messenger RNA (mRNA) vaccines, particularly vaccines against the SARS–CoV–2 coronavirus.

METHODS:

Study designs: Evidence–based clinical practice guidelines issued by professional societies and national health systems, systematic reviews. Large primary studies will be reviewed if systematic reviews are lacking.

Inclusion and exclusion criteria:

Participants: Adults. Persons in high–risk groups will be analyzed separately if evidence permits. Interventions: Immunization using a lipid–encapsulated mRNA vaccine. Vaccines against the SARS–CoV–2 coronavirus are of particular interest. Comparisons: Not applicable. Outcomes: Vaccine–related adverse events. Timing: As reported by investigators. Setting: All settings. Other: Published in English Data collection Databases: NICE Evidence Search, ECRI Guidelines Trust, CADTH, INAHTA, Cochrane Library, web sites of relevant professional
organizations, Medline, EMBASE Data synthesis (calculation of relative risks and confidence intervals, meta–analyses, exploration of heterogeneity): Qualitative. NOTE: CEP standard review methods, including scales for quality assessment of guidelines, systematic reviews, and primary studies can be found in the Methods section of the CEP web site. (www.uphs.upenn.edu/cep/methods)

Results  

We found no guidelines regarding patient groups for whom mRNA vaccines should be avoided or other guidelines specific to mRNA vaccines. This is likely due to the lack of FDA or European approval for any mRNA vaccines before this month. General guidance on COVID–19 vaccination has been issued by Public Health England (Table 11). It is of low quality (Table 12) and based on limited evidence.

Because no clinical trials involving children have been reported yet, and children have less risk of serious illness or death from COVID–19, vaccination of children is not recommended. For a summary of guidance on COVID–19 vaccines for women who are pregnant or breastfeeding, please see the CEP Rapid Guidance Summary on that topic.

Systematic reviews

Two systematic reviews of SARS–CoV–2 vaccines were found by our searches (Table 13, Table 14). The first (3) was published in May 2020 with searches completed April 17, 2020. At that time, only one trial of an mRNA vaccine was found, and results of it had not been reported. The second systematic review (4) has not been peer–reviewed and published, but a preprint of the authors’
manuscript was posted to the medRxiv server on November 4, with searches completed on October 20.

Five trials were meta–analyzed in this review, but only one of them (5) involved an mRNA vaccine. That trial was very small, and while it found a higher rate of adverse events in the vaccine group than in the placebo group, that difference was not statistically significant. All of the reported adverse events were minor, most were localized, and all resolved within days. A “living” systematic review of COVID–19 vaccine studies is planned; its protocol was published in November 2020 (6).

Serious adverse events will be a primary outcomes measure of the review, and minor adverse events will be a secondary outcome. There is no project website reported yet.

Primary studies

Because of the urgent nature of the topic and the absence of high–level evidence, we proceeded to review and analyze results from primary studies of mRNA vaccines (Table 15). All of the mRNA vaccine safety data published to date is from early–phase clinical trials. Some of the data comes from non–peer–reviewed and unpublished manuscripts, as noted in the table. This data should be used with caution.

The studies are all small: they lack sufficient power to detect and assess the probability of uncommon adverse events, so the absence of such events in these trials should not be taken as evidence these events may not happen when mRNA vaccines are used more widely. Phase III trials that may yield more information on these events are in progress (Table 16) but their results should not be
expected until mid–2021.

Because the trials published to date were small, and done in part to optimize dosing, we will analyze their results only qualitatively. No serious events as defined in FDA guidance (life–threatening, disabling, or requiring hospitalization) were reported in any of the trials. However, both systemic adverse events such as fatigue, headache, muscle aches, and chills; and localized adverse events such as pain at the injection site were very common in all of the trials.

Most of the adverse events were mild, and resolved within one or two days. Serious events, defined as events that temporarily interfered with subjects’ everyday activities, were reported by
approximately 5 to 10 percent of study subjects. These too resolved within one or two days. While there is not sufficient data to statistically test these observations, a few trends are seen in the data.

First, the rate of adverse events and the rate of serious adverse events were higher after a subject’s second injection compared to the first one. Second, subjects receiving higher doses of the vaccine reported more adverse events and more severe adverse events. There is a possible trend towards a reduced rate of adverse events in older subjects than in younger ones.

There is not sufficient data to permit any conclusions about the comparative safety of specific vaccines. While one study reported on mRNA influenza vaccines and another reported on a respiratory syncytial virus vaccine, there is not sufficient evidence to draw more generalized comparisons of the safety of mRNA vaccines compared to other types of vaccines.

Trials in progress

Table 13 lists mRNA vaccine clinical trials registered in ClinicalTrials.gov that are expected to enroll 500 or more subjects. These will yield additional safety data once they are completed. The one relevant trial found in the European Clinical Trials Registry was also included in the US registry. No clinical trials of mRNA vaccines against pathogens other than SARS–CoV–2 have reached the
500 subject threshold.

Conclusions

The current evidence base on messenger RNA (mRNA) vaccines is made up entirely of small early–stage trials, nearly all of which examined only short–term outcomes. They lack sufficient power for testing the statistical significance of most results, and for assessing the risk of serious but uncommon adverse events.

The size of these trials and their dual purpose in evaluating dosing and safety precludes quantitative synthesis or GRADE analysis of their results, but there are a few trends that appear to be consistent across the different studies. Systemic adverse effects such as fatigue, headache, muscle aches, and chills are common following administration of mRNA vaccines, but they usually resolve within a day or two.

Localized adverse effects, most notably pain at the injection site, are also common, and also resolve within a day or two. The rate of severe adverse effects (severe enough to interfere with a person’s daily activities) appears to be in the range of 5 to 10 percent. The rate and severity of adverse events increases with vaccine dose. The rate and severity of adverse events also appears to
be greater following a second dose of vaccine than following the first.

Larger clinical trials of mRNA vaccines against the SARS–CoV–2 coronavirus are in progress, and their results are expected in mid–2021. Once evidence from those trials is published, more certain conclusions about the safety of these vaccines may be reached. Additional trials will be necessary to determine the relative safety of mRNA vaccines and vaccines using more established
technologies.

Clinical guidance specific to the use of mRNA vaccines is lacking at this time, because of the lack of clinical evidence.

Conflict of interest disclosures

None of the authors have any relevant financial relationships with commercial interests associated with the subject of this review. The CEP conflict of interest disclosure policy is found at www.uphs.upenn.edu/cep/methods. CEP reports are funded by the University of Pennsylvania Health System.

See more here: uphs.upenn.edu

Header image: Scentpression

Editor’s note: This article was originally published in December 2020.

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